Pharmacological research最新文献_第3页

Response to Letter to the Editor: Letter by Ru and Zhang regarding article, "Plasma miR-150-5p as a biomarker for immunosuppressive therapy response in acetylcholine receptor positive myasthenia gravis: a long-term prospective longitudinal study". 回复编辑：Ru和Zhang关于“血浆miR-150-5p作为免疫抑制治疗反应的生物标志物在乙酰胆碱受体阳性重症肌无力：一项长期前瞻性纵向研究”这篇文章的来信。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-29 DOI: 10.1016/j.phrs.2026.108116

Nemanja Garai, Sanja Madic, Vukan Ivanovic, Aleksa Palibrk, Jovan Pesovic, Milos Brkusanin, Ivana Basta, Stojan Peric, Dusanka Savic-Pavicevic

引用次数: 0

Pain signaling via sensory neurons drives breast cancer progression through neuropeptide release and κ-opioid counter-regulation. 感觉神经元的疼痛信号通过神经肽释放和κ-阿片反调控驱动乳腺癌进展。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-28 DOI: 10.1016/j.phrs.2026.108113

Hitoshi Makabe, Michiko Narita, Yasuyuki Nagumo, Masanori Fujiwara, Yusuke Hamada, Jion Takise, Takumi Yoshizawa, Sakura Sano, Shin Iizuka, Eri Asaba, Yukari Suda, Tomohisa Mori, Tsuyoshi Saitoh, Hiroshi Nagase, Vivianne L Tawfik, Shigehiro Yagishita, Akinobu Hamada, Kan Yonemori, Shin Takayama, Masayuki Yoshida, Ryo Yoshizawa, Kenichi G N Suzuki, Rinshi S Kasai, Naoko Kuzumaki, Eriko Satomi, Minoru Narita

Severe pain in patients with breast cancer is associated with poorer survival outcomes, yet the mechanisms linking nociceptive signaling to tumor progression remain unclear. In a clinical cohort, breast cancer patients whose moderate or severe pain improved under specialized palliative care exhibited significantly longer survival than those with persistent pain. Serum levels of calcitonin gene-related peptide (CGRP) and substance P (SP), neuropeptides that can be released from sensory neurons, were elevated in breast cancer patients with uncontrolled pain, correlating positively with pain intensity and negatively with overall survival. In vitro, supernatants from depolarized human iPSC-derived sensory neurons containing CGRP, SP, and the endogenous κ-opioid receptor (KOR) ligand dynorphin attenuated docetaxel efficacy, promoted epithelial-mesenchymal transition, and enhanced migration in human triple-negative breast cancer (TNBC) cells, accompanied by Gi protein-coupled activation of the PI3K-Akt signaling pathway. In vivo, optogenetic activation of sensory neurons significantly accelerated tumor growth following orthotopic transplantation of murine TNBC cells, whereas combined blockade of CGRP and SP receptors suppressed this effect. Similarly, in patient-derived xenograft models of TNBC, dual receptor blockade effectively abrogated tumor progression. Conversely, in vitro treatment with dynorphin enhanced the cytotoxic efficacy of docetaxel, accompanied by the inhibition of PI3K-Akt signaling, whereas in vivo administration of the peripherally restricted KOR agonist nalfurafine methiodide markedly suppressed tumor growth. These findings establish a bidirectional neural-tumor axis in breast cancer progression. Therapeutically, combined blockade of CGRP/SP signaling with peripheral KOR agonism may present a novel strategy to enhance chemotherapy efficacy in TNBC patients.

乳腺癌患者的剧烈疼痛与较差的生存结果相关，但伤害性信号传导与肿瘤进展之间的机制尚不清楚。在一项临床队列研究中，在专门姑息治疗下，中度或重度疼痛得到改善的乳腺癌患者的生存期明显长于持续性疼痛患者。可从感觉神经元释放的神经肽降钙素基因相关肽（CGRP）和P物质（SP）的血清水平在疼痛失控的乳腺癌患者中升高，与疼痛强度呈正相关，与总生存期呈负相关。在体外，从含有CGRP、SP和内源性κ-阿片受体（KOR）配体dynorphin的去极化人ipsc来源的感觉神经元中提取的上清液在人三阴性乳腺癌（TNBC）细胞中减弱了多西他赛的疗效，促进了上皮-间质转化，并增强了迁移，同时伴有Gi蛋白偶联激活PI3K-Akt信号通路。在体内，感觉神经元的光遗传学激活显著加速了小鼠TNBC细胞原位移植后的肿瘤生长，而联合阻断CGRP和SP受体则抑制了这一作用。同样，在患者来源的TNBC异种移植模型中，双受体阻断有效地消除了肿瘤进展。相反，dynorphin在体外可增强多西紫杉醇的细胞毒作用，同时抑制PI3K-Akt信号，而在体内给药外周限制性KOR激动剂纳氟萘芬可显著抑制肿瘤生长。这些发现在乳腺癌进展中建立了双向神经-肿瘤轴。在治疗上，联合阻断CGRP/SP信号与外周KOR激动作用可能是提高TNBC患者化疗疗效的新策略。

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引用次数: 0

The SAM-m6A axis as an unexplored therapeutic hub for plant-derived regulation of disease metabolism SAM-m6A轴作为植物源性疾病代谢调节的一个未开发的治疗中枢

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-28 DOI: 10.1016/j.phrs.2026.108114

Yuxuan Zhao , Jingyimei Liang , Wanning Ma , Jianbo Xiao , Hui Cao

S-adenosylmethionine (SAM) is the main cellular methyl donor and a core product of one-carbon metabolism. Its balance with S-adenosylhomocysteine (SAH) defines methylation potential and shapes epigenetic and epitranscriptomic outputs. RNA N⁶-methyladenosine (m⁶A) directly depends on SAM and is controlled by a writer-reader-eraser system. This review summarizes how altered SAM supply, SAH accumulation, and shifts in the SAM/SAH ratio can reprogram m⁶A landscapes. These changes can occur in cancer, metabolic disease, inflammation, and neurodegeneration. We integrate metabolic control of SAM generation and consumption with regulation of METTL3/METTL14, WTAP and related cofactors, and the erasers FTO and ALKBH5. We also assess plant-derived bioactive compounds proposed to act on this coupling. Most phytochemicals do not behave as potent, selective m⁶A enzyme inhibitors. They more often act upstream by reshaping one-carbon metabolism, redox state, and protein expression. This profile contrasts with canonical synthetic inhibitors that block a single node with higher affinity and more predictable pharmacodynamics. Together, the evidence supports the SAM-m⁶A axis as a practical framework to connect nutrient state with RNA fate decisions. It also highlights key gaps for translation, including target engagement, dose-exposure alignment, and causal validation of m⁶A-dependent phenotypes.

s -腺苷甲硫氨酸（SAM）是主要的细胞甲基供体，是单碳代谢的核心产物。它与s -腺苷型同型半胱氨酸（SAH）的平衡决定了甲基化潜能，并决定了表观遗传和表转录组输出。RNA n6 -甲基腺苷（m6A）直接依赖于SAM，并由写入-读取-擦除系统控制。这篇综述总结了SAM供应、SAH积累和SAM/SAH比值的变化是如何重新编程m6A景观的。这些变化可能发生在癌症、代谢性疾病、炎症和神经变性中。我们将SAM生成和消耗的代谢控制与METTL3/METTL14、WTAP和相关辅因子以及FTO和ALKBH5的调控结合起来。我们还评估了植物衍生的生物活性化合物，建议对这种偶联起作用。大多数植物化学物质不表现为有效的，选择性的m6A酶抑制剂。它们更常通过重塑单碳代谢、氧化还原状态和蛋白质表达而上游作用。这与典型的合成抑制剂形成对比，后者阻断单个节点，具有更高的亲和力和更可预测的药效学。总之，证据支持SAM-m6A轴作为连接营养状态与RNA命运决定的实用框架。它还强调了翻译的关键空白，包括靶标接合、剂量暴露校准和m6a依赖性表型的因果验证。

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引用次数: 0

From gasotransmitter to therapeutic insight: Unraveling the role of H₂S in the gut-liver axis during NAFLD 从气体递质到治疗洞察：揭示H₂S在NAFLD中肠-肝轴的作用。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-23 DOI: 10.1016/j.phrs.2026.108108

Huimin Kang , Yongjia Feng , Baodong Wang , Zheng Chen , Jingya Li , Zhiyun Chen

Non-alcoholic fatty liver disease (NAFLD) is a widespread chronic liver condition with intricate pathogenesis and poses substantial challenges for clinical management. The gut-liver axis is integral to the pathogenesis of NAFLD, and hydrogen sulfide (H₂S), a gaseous signaling molecule, offers novel insights into its pathophysiology. This review investigates the characteristics of H₂S within the gut and liver at the gut-liver axis level, examines the role of gut-liver interactions in NAFLD, and evaluates the potential function of H₂S as a crucial link in the pathogenesis of NAFLD via the gut-liver axis. By analyzing the role of H₂S within the gut-liver axis, this review highlights its potential therapeutic value in NAFLD, thereby providing a critical theoretical foundation for advancing the understanding of NAFLD's pathophysiological mechanisms and the development of novel targeted therapies.

非酒精性脂肪性肝病（NAFLD）是一种广泛存在的慢性肝病，其发病机制复杂，对临床治疗提出了重大挑战。肠-肝轴是NAFLD发病机制中不可或缺的一部分，硫化氢（H₂S），一种气体信号分子，为其病理生理学提供了新的见解。本文从肠-肝轴水平研究了H₂S在肠道和肝脏内的特征，探讨了肠-肝相互作用在NAFLD中的作用，并评估了H₂S作为肠-肝轴在NAFLD发病中的关键环节的潜在功能。本文通过分析H₂S在肠-肝轴中的作用，强调其在NAFLD中的潜在治疗价值，从而为进一步了解NAFLD的病理生理机制和开发新的靶向治疗方法提供重要的理论基础。

引用次数: 0

Xiaoyaosan and isoliquiritigenin remodel depression-associated chromatin 3D structure and phase separation of NF-κB p65 消药散和异尿素重塑抑郁相关的染色质三维结构和NF-κB1相分离。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-23 DOI: 10.1016/j.phrs.2026.108111

Lili Fan , Xiaowei Mo , Ranran Dai , Jingman Tang , Chunmiao Wan , Shaoyi Fang , Xuan Zhou , Qingyu Ma , Xuxu Zhuang , Yueyue Chen , Xiaojuan Li , Jiaxu Chen

Xiaoyaosan (XYS) is a classical traditional prescription with well-documented antidepressant effects. However, the active components and molecular mechanisms to alleviate depression remain unclear. In this study, using chronic social defeat stress (CSDS) and lipopolysaccharide (LPS)-induced depression models, we found that XYS and its key ingredient isoliquiritigenin (ILG) not only significantly improved depressive-like behaviors in mice but also exerted dual regulatory effects at the cellular level, promoting hippocampal neural stem cell proliferation and differentiation, while inhibiting microglia-mediated neuroinflammation. Using Hi-C technology, we discovered that XYS and ILG reversed the abnormal chromatin 3D structure in hippocampal microglia of depression models. Integrated analyses of transcriptomics, molecular docking, and 3D genomics identified the transcription factor p65 as a target of XYS and ILG. Co-culture experiments with microglia and neural stem cells further confirmed that overexpression of p65 promotes inflammation and inhibits neuronal growth. In depressed mice, NF-κB p65 expression was elevated and further formed phase separated condensates, which was effectively suppressed by XYS and ILG. This study reveals how XYS and its active component ILG function mechanistically to exert therapeutic effects on depression, including restoring chromatin 3D structure, and normalizing pathological phase separation of NF-κB p65, and reversing depressive phenotypes. Collectively, these findings provide a solid experimental foundation for the development of natural antidepressants.

消药散是一种经典的传统处方，具有良好的抗抑郁作用。然而，其有效成分和分子机制仍不清楚。本研究利用慢性社会失败应激（CSDS）和脂多糖（LPS）诱导的抑郁模型，发现XYS及其关键成分异利基素（ILG）不仅显著改善小鼠抑郁样行为，而且在细胞水平上发挥双重调节作用，促进海马神经干细胞的增殖和分化，同时抑制小胶质细胞介导的神经炎症。利用Hi-C技术，我们发现XYS和ILG逆转了抑郁症模型海马小胶质细胞异常的染色质3D结构。转录组学、分子对接和3D基因组学的综合分析确定了转录因子Nfkb1是XYS和ILG的靶标。小胶质细胞和神经干细胞共培养实验进一步证实，Nfkb1高表达可促进炎症，抑制神经元生长。在抑郁小鼠中，NF-κB1表达升高并进一步形成相分离凝析物，XYS和ILG可有效抑制其表达。本研究揭示了XYS及其活性成分ILG对抑郁症的作用机制，包括恢复染色质3D结构，使NF-κB1病理相分离正常化，逆转抑郁表型。总的来说，这些发现为开发天然抗抑郁药提供了坚实的实验基础。

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引用次数: 0

Immunometabolic reprogramming of macrophages: Emerging roles in skeletal muscle regeneration and therapeutic perspectives 巨噬细胞的免疫代谢重编程：在骨骼肌再生和治疗方面的新作用

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-21 DOI: 10.1016/j.phrs.2026.108109

Si-jing Li , Xing-ling He , Xiao-jiao Zhang , Zi-ru Li , Hui-lin Liu , Yi-hui Zhang , Min-qi Lu , Jia-hui Chen , Xiao-ming Dong , Wen-jie Long , Lu Lu , Zhong-qi Yang , Shi-hao Ni

Skeletal muscle regeneration is a complex and strictly regulated process that involves complex interactions between immune cells, muscle-resident progenitor cells, and stromal components. Macrophages play a central role in this process by coordinating immune responses, supporting regeneration, and promoting tissue remodeling through phenotypic transitions that respond to environmental cues. Under physiological conditions, these transitions ensure efficient tissue restoration. However, in pathological settings or conditions such as aging, muscular dystrophy, cancer cachexia, and metabolic disorders, macrophage function becomes dysregulated. This situation often leads to persistent inflammation, excessive fibrosis, and impaired regeneration of muscle tissue. Recent advances in single-cell and spatial transcriptomics technologies have revealed the remarkable heterogeneity of macrophage subpopulations within skeletal muscle. These findings emphasize the importance of immunometabolic programming as a key driver of macrophage plasticity. Shifts in glucose metabolism, oxidative phosphorylation, lipid utilization, and amino acid pathways critically influence the polarization of macrophages and their interactions with surrounding cells. Moreover, metabolic signals from the tissue microenvironment, circulating factors, and muscle-resident cells create a dynamic network of metabolic crosstalk that shapes macrophage behavior. This review provides a comprehensive summary of how macrophage immunometabolism regulates skeletal muscle regeneration in both acute injury and chronic disease. It highlights core metabolic pathways, macrophage-centered intercellular communication, and emerging therapeutic strategies that aim to reprogram macrophage metabolism for a regenerative benefit. In addition, key challenges and future directions for translating these insights into effective interventions for muscle wasting conditions are discussed.

骨骼肌再生是一个复杂的、严格调控的过程，涉及免疫细胞、肌内祖细胞和基质成分之间复杂的相互作用。巨噬细胞在这一过程中发挥核心作用，协调免疫反应，支持再生，并通过响应环境线索的表型转变促进组织重塑。在生理条件下，这些转变确保了有效的组织修复。然而，在病理环境或条件下，如衰老、肌肉萎缩、癌症恶病质和代谢紊乱，巨噬细胞功能变得失调。这种情况通常会导致持续的炎症、过度纤维化和肌肉组织再生受损。单细胞和空间转录组学技术的最新进展揭示了骨骼肌内巨噬细胞亚群的显著异质性。这些发现强调了免疫代谢编程作为巨噬细胞可塑性关键驱动因素的重要性。葡萄糖代谢、氧化磷酸化、脂质利用和氨基酸途径的变化严重影响巨噬细胞的极化及其与周围细胞的相互作用。此外，来自组织微环境、循环因子和肌肉驻留细胞的代谢信号创建了一个动态的代谢串扰网络，形成巨噬细胞的行为。本文综述了巨噬细胞免疫代谢在急性损伤和慢性疾病中如何调节骨骼肌再生。它强调了核心代谢途径，以巨噬细胞为中心的细胞间通讯，以及旨在重编程巨噬细胞代谢以获得再生益处的新兴治疗策略。此外，讨论了将这些见解转化为有效干预肌肉萎缩条件的关键挑战和未来方向。

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引用次数: 0

YBX1-LDHB axis orchestrates pyruvate production from lactate to promote ICC initiation and development YBX1-LDHB轴协调乳酸生成丙酮酸，促进ICC的发生和发展

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-21 DOI: 10.1016/j.phrs.2026.108110

Yong Liu , Fei Wang , Mi Zhang , Xiabing Shi , Lei Li , Tingjie Wang , Haifeng Zhang , Zhongyu Cheng , Xiangpan Li , Juan Chen , Chuanrui Xu

Previous work from our group established that Y-box binding protein 1 (YBX1) plays a pivotal role in the initiation and progression of intrahepatic cholangiocarcinoma (ICC); however, its specific biological functions and underlying regulatory mechanisms remain unclear. The current study demonstrates that YBX1 is highly expressed in ICC tissues, and its highly expression correlates significantly with a poor prognosis in patients with ICC. In vitro experiments revealed that YBX1 overexpression significantly enhanced the proliferation of ICC cells. Conversely, YBX1 knockout robustly inhibited tumor growth in both in vitro and in vivo models. Mechanistically, YBX1 upregulated the expression of lactate dehydrogenase B (LDHB) by increasing its transcriptional activity and stabilizing LDHB mRNA. Elevated LDHB expression drives the conversion of lactate to pyruvate, which is further metabolized to acetyl coenzyme A. This metabolic reprogramming enhances the activity of tricarboxylic acid (TCA) cycle and production of adenosine triphosphate, thereby providing essential energy support for the proliferation of ICC cells. Corroboratively, inhibiting LDHB via CRISPR-Cas9-mediated knockout suppressed ICC cell proliferation, whereas LDHB overexpression accelerated the ICC tumor progression. Lactate induces YBX1 nuclear translocation, which in turn activates LDHB transcription. Collectively, our findings demonstrate the oncogenic roles of YBX1 and LDHB in ICC progression, identify lactate as a key energy source sustaining the activity of TCA cycle and oxidative phosphorylation, and highlight the YBX1-LDHB axis as a potential therapeutic target.

本小组前期工作证实，Y-box结合蛋白1 （YBX1）在肝内胆管癌（ICC）的发生和发展中起关键作用；然而，其具体的生物学功能和潜在的调控机制尚不清楚。本研究表明YBX1在ICC组织中高表达，其高表达与ICC患者预后不良显著相关。体外实验表明，YBX1过表达可显著促进ICC细胞的增殖。相反，在体外和体内模型中，YBX1敲除均能显著抑制肿瘤生长。在机制上，YBX1通过增加乳酸脱氢酶B （LDHB）的转录活性和稳定LDHB mRNA来上调其表达。升高的LDHB表达驱动乳酸转化为丙酮酸，丙酮酸进一步代谢为乙酰辅酶a。这种代谢重编程增强了三羧酸（TCA）循环的活性和三磷酸腺苷的产生，从而为ICC细胞的增殖提供必需的能量支持。证实，通过crispr - cas9介导的敲除抑制LDHB抑制ICC细胞增殖，而LDHB过表达加速ICC肿瘤进展。乳酸诱导YBX1核易位，进而激活LDHB转录。总之，我们的研究结果证明了YBX1和LDHB在ICC进展中的致癌作用，确定了乳酸是维持TCA循环和氧化磷酸化活性的关键能量来源，并强调了YBX1-LDHB轴是潜在的治疗靶点。

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引用次数: 0

Gene modification: Exploring the potential in treating kidney diseases 基因修饰：探索治疗肾脏疾病的潜力。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-17 DOI: 10.1016/j.phrs.2026.108104

Ubong S. Ekperikpe, Serena Zhao, Ilse S. Daehn

Chronic kidney disease (CKD) is a leading cause of death worldwide. Currently available drugs slow but do not cure or prevent progression to end-stage kidney disease. Unfortunately, dialysis and kidney transplant not only pose severe lifestyle constraints and healthcare costs on patients but are also associated with side effects such as electrolyte abnormalities and increased susceptibility to infections. It is imperative to research new therapeutic strategies for the management of CKD. Technological advances in genetics and genomics in recent years have revealed the role that genetics plays in CKD pathophysiology, suggesting that gene therapies may be a viable therapeutic strategy for the management of CKD. Over the years, there has been an increase in new gene therapies approved for various indications; however, none are currently approved for kidney diseases. As our understanding of the genetics of kidney diseases grows, together with emerging gene modifying technologies and delivery tools improve, there is hope that a new generation of gene therapies may become available in the future. In this review, we describe the mechanisms of action and delivery strategies of recent gene editing technologies, after which we explore the potential of gene therapies for kidney diseases. We also discuss noteworthy adverse effects associated with gene therapies and explore the use of emerging artificial intelligence and machine learning in opening new avenues for precision editing towards treatment of kidney diseases. We conclude by discussing the challenges that may impact the development of gene therapies, along with a perspective on how the current landscape may influence the adoption of these strategies for kidney diseases.

慢性肾脏疾病（CKD）是世界范围内导致死亡的主要原因。目前可用的药物减缓但不能治愈或防止进展到终末期肾脏疾病。不幸的是，透析和肾移植不仅给患者带来了严重的生活方式限制和医疗保健费用，而且还与电解质异常和感染易感性增加等副作用有关。研究新的CKD治疗策略势在必行。近年来遗传学和基因组学的技术进步揭示了遗传学在CKD病理生理中的作用，提示基因治疗可能是CKD管理的可行治疗策略。多年来，针对各种适应症批准的新基因疗法有所增加；然而，目前没有一种药物被批准用于肾脏疾病。随着我们对肾脏疾病遗传学的理解不断加深，加上新兴的基因修饰技术和传递工具的改进，新一代的基因疗法有望在未来成为可能。在这篇综述中，我们描述了最近基因编辑技术的作用机制和传递策略，然后我们探索了肾脏疾病基因治疗的潜力。我们还讨论了与基因疗法相关的值得注意的不良反应，并探索了新兴的人工智能和机器学习的使用，为精确编辑治疗肾脏疾病开辟了新的途径。最后，我们讨论了可能影响基因治疗发展的挑战，以及当前形势如何影响这些策略在肾脏疾病中的应用。

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引用次数: 0

Mitochondrial semi-autonomous inheritance in cardiovascular pathology: Emerging mechanisms and therapeutic opportunities 线粒体半自主遗传在心血管病理：新出现的机制和治疗机会。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-17 DOI: 10.1016/j.phrs.2026.108106

Xinyue Xie , Tianhang Yu , Wei Deng , Saiyang Xie

Cardiovascular diseases (CVDs) continue to be a leading contributor to morbidity and mortality worldwide, with mitochondrial dysfunction emerging as a key pathological hallmark. As semi-autonomous organelles, mitochondria regulate cellular energy metabolism and homeostasis through intricate interactions between nuclear and mitochondrial genomes. This review synthesizes recent advances in understanding mitochondrial semi-autonomous inheritance mechanisms in cardiac pathology, encompassing mtDNA dynamics, epigenetic and non-epigenetic modifications, mtDNA release-induced inflammation, and mito-nuclear communication. Impaired regulation of the aforementioned processes causes disruption to the mitochondrial function, inducing cardiac remodeling and CVD progression. Here, we reveal novel therapeutic opportunities, including natural and pharmaceutical modulators, mitochondrial gene-editing technologies, and ncRNA-based interventions which can potentially restore mitochondrial homeostasis. Moreover, several challenges such as achieving precise drug targeting and implementation of real-time efficacy monitoring remain to be resolved. Future research should develop strategies to close these gaps, identify the context-dependent mechanisms, and advance translational applications to improve the prognosis of CVDs.

心血管疾病（cvd）仍然是世界范围内发病率和死亡率的主要原因，线粒体功能障碍是一个关键的病理标志。作为半自主的细胞器，线粒体通过细胞核和线粒体基因组之间复杂的相互作用来调节细胞的能量代谢和稳态。本文综述了心脏病理中线粒体半自主遗传机制的最新进展，包括mtDNA动力学、表观遗传和非表观遗传修饰、mtDNA释放诱导的炎症和有丝分裂核通讯。上述过程的调节受损导致线粒体功能的破坏，诱导心脏重塑和心血管疾病的进展。在这里，我们揭示了新的治疗机会，包括天然和药物调节剂、线粒体基因编辑技术和基于ncrna的干预，这些干预可能恢复线粒体稳态。此外，实现精确的药物靶向和实施实时疗效监测等几个挑战仍有待解决。未来的研究应该制定策略来缩小这些差距，确定环境依赖的机制，并推进转化应用以改善心血管疾病的预后。

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引用次数: 0

A CARM1-targeted therapeutic peptide suppresses breast cancer progression both in vitro and in vivo 一种靶向carm1的治疗肽在体内和体外均可抑制乳腺癌的进展。

IF 10.5 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research

Pub Date : 2026-01-16 DOI: 10.1016/j.phrs.2026.108105

Bing-ling Peng , Jun Hong , Zi-rui Wang , Zao-zao Zheng , Jian-cheng Ding , Jia-ying Zhou , Ting Ran , Wen Liu

Coactivator-associated arginine methyltransferase 1 (CARM1/PRMT4) is well-known for its essential physiological functions and its pivotal role in the development and progression of various cancers. Targeted inhibition of CARM1 activity has emerged as a promising strategy for cancer treatment. Herein, we report a peptide inhibitor of CARM1 designated as Pi-CARM1, which demonstrates high selectivity for CARM1. The cell-permeable variant, Pi-CARM1 modified with Trans-Activator of Transcription sequence (Pi-CARM1-TAT), effectively inhibits breast cancer cell proliferation in vitro and significantly reduces tumor growth in mouse models of breast cancer. Mechanistically, Pi-CARM1-TAT recapitulates the impact of CARM1 on the expression of oncogenic estrogen/ERα-target genes, as well as type I interferon (IFN) and IFN-induced genes (ISGs) in breast cancer cells. Notably, the combination of Pi-CARM1-TAT with endocrine therapy drugs or etoposide shows synergistic effects in inhibiting breast tumorigenesis. Furthermore, Pi-CARM1-TAT effectively overcomes endocrine therapy resistance in ER-positive breast cancer cells. In conclusion, we present a novel peptide inhibitor of CARM1, which provides valuable insights and may offer therapeutic potential for the development of CARM1-targeted treatments in breast cancer.

Coactivator-associated arginine methyltransferase 1 （CARM1/PRMT4）因其重要的生理功能和在各种癌症的发生和进展中的关键作用而闻名。靶向抑制CARM1活性已成为一种很有前途的癌症治疗策略。在此，我们报道了一种CARM1的肽抑制剂Pi-CARM1，它对CARM1具有高选择性。细胞渗透性变体Pi-CARM1经转录反式激活子序列修饰（Pi-CARM1- tat），在体外有效抑制乳腺癌细胞增殖，并显著降低乳腺癌小鼠模型中的肿瘤生长。在机制上，Pi-CARM1-TAT概括了CARM1对乳腺癌细胞中致癌雌激素/ er α靶基因以及I型干扰素（IFN）和IFN诱导基因（ISGs）表达的影响。值得注意的是，Pi-CARM1-TAT与内分泌治疗药物或依托泊苷联用在抑制乳腺肿瘤发生方面具有协同作用。此外，Pi-CARM1-TAT可有效克服er阳性乳腺癌细胞的内分泌治疗耐药。总之，我们提出了一种新的CARM1肽抑制剂，这为乳腺癌CARM1靶向治疗的发展提供了有价值的见解，并可能提供治疗潜力。

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引用次数: 0